A Systematic Review on the Potential Acceleration of Neurocognitive Aging in Older Cancer Survivors

Simple Summary As survival rates for cancer increase and most patients exceed the age of 65 years, more emphasis has gone to possible cognitive sequelae, which could be explained by accelerated brain aging. We conducted a systematic literature review to summarize the existing risks of cognitive decline, imaging-based indication of neurotoxicity, as well as developing a neurodegenerative disease in older cancer survivors. Evidence was found for functional and structural brain changes. Cognitive decline was mainly found in memory functioning. Individual risk factors included cancer types (brain, hormone-related cancers), treatment (anti-hormonal therapy, chemotherapy, cranial radiotherapy), genetic predisposition (APOE, COMT, BDNF), increasing age, comorbidities (frailty, baseline cognitive reserve, functional decline), and psychological (distress, depression, anxiety, post-traumatic stress disorder, sleeping problems, fatigue) and social factors (loneliness, caregiver support, socioeconomic status). Further research is needed to provide a more detailed and profound picture of accelerated neurocognitive aging in specific older subpopulations and targeted interventions. Abstract As survival rates increase, more emphasis has gone to possible cognitive sequelae in older cancer patients, which could be explained by accelerated brain aging. In this review, we provide a complete overview of studies investigating neuroimaging, neurocognitive, and neurodegenerative disorders in older cancer survivors (>65 years), based on three databases (Pubmed, Web of Science and Medline). Ninety-six studies were included. Evidence was found for functional and structural brain changes (frontal regions, basal ganglia, gray and white matter), compared to healthy controls. Cognitive decline was mainly found in memory functioning. Anti-hormonal treatments were repeatedly associated with cognitive decline (tamoxifen) and sometimes with an increased risk of Alzheimer’s disease (androgen deprivation therapy). Chemotherapy was inconsistently associated with later development of cognitive changes or dementia. Radiotherapy was not associated with cognition in patients with non-central nervous system cancer but can play a role in patients with central nervous system cancer, while neurosurgery seemed to improve their cognition in the short-term. Individual risk factors included cancer subtypes (e.g., brain cancer, hormone-related cancers), treatment (e.g., anti-hormonal therapy, chemotherapy, cranial radiation), genetic predisposition (e.g., APOE, COMT, BDNF), age, comorbidities (e.g., frailty, cognitive reserve), and psychological (e.g., depression, (post-traumatic) distress, sleep, fatigue) and social factors (e.g., loneliness, limited caregiver support, low SES). More research on accelerated aging is required to guide intervention studies.


Introduction
In 2020, the worldwide incidence of cancer was 19.3 million [1]. Thanks to improvement in treatments, as well as earlier detection, survival rates have increased, resulting in more long-term and older survivors of cancer [2][3][4]. Hence, quality of life in survivorship of these patients has become an important topic in cancer research. While the older population of cancer survivors is the largest, most neurocognitive studies do not focus on this specific population. It is important to understand the long-term effects of cancer and its treatment on the neurocognitive aging process of this older population of survivors [2]. One such long-term effect entails neurocognitive decline, which is an important factor contributing to quality of life (QoL) [5]. Cognitive deficits are mostly summarized under the term "cancer-related cognitive impairment (CRCI)". CRCI was described earlier by Janelsins and colleagues (2014) as immediate or delayed cognitive difficulties after cancer and its treatment, including perceived and objective decline in memory, attention, concentration, and executive function [6].
The involved neurotoxic mechanisms can be treatment-specific (e.g., radiotherapy, chemotherapy, and immunotherapy), but overlap between these mechanisms exists. For instance, the possible mechanisms of chemotherapy-induced cognitive changes include decreased integrity of the blood-brain barrier, neuronal apoptosis and reduced neurogenesis, DNA damage, inflammation and cytokine deregulation, reduced estrogen and testosterone levels, cardiotoxic effects, neuroendocrine changes, and genetic predispositions [7]. More recently, Makale and colleagues (2017) reviewed possible central neurotoxic mechanisms of cranial irradiation. These similarly cover changes of neuronal apoptosis and reduced neurogenesis, inflammation and damage to neuronal dendrite structures, and prefrontal cortex damage (white matter, vessels, and neurons) [8]. Joly et al. (2020) studied potential central neurotoxic mechanisms of immunotherapy. Higher pro-inflammatory cytokines and growth factors, cytokine dysregulation, increase in T-cell receptor diversity, and white blood cell count could all have an adverse effect on immune-related events affecting all organs of the body. All these processes could indirectly cause neural degeneration as well. However, evidence regarding neuropsychological outcomes post-immunotherapy remains scarce [9,10].
In most people, the cognitive deficits and/or complaints tend to resolve within the first few months after treatment, but in about a third of survivors, the cognitive deficits and/or complaints can persist longer [11]. Confounding factors such as sociodemographic factors (e.g., age, cognitive reserve, socioeconomic status, education), genetics, physical conditions (e.g., comorbidities, frailty, postmenopausal status), and psychological factors (e.g., fatigue, emotional distress, allostatic load and lifestyle) can further explain daily life functioning [12][13][14]. The multifactorial nature causes some people to be more at risk for cognitive impairment than others and complicates the identification of responsible components for changes in cognition, which can even be more elevated in older patients [12,15].
Aging occurs throughout an individual's lifespan. Normal biological aging involves the accumulation of damage on the molecular and cellular level over time, resulting in a deterioration of physical and mental capacities and an increased vulnerability to disease [15]. The cellular mechanisms involved in this process include DNA damage and mutations, epigenetic aging, stem cell damage (oxidative stress), cellular senescence (telomere shortening), and inflammation. Each of these can contribute to neurocognitive aging and cognitive decline [16]. Cancer, of which dysregulated cell growth is one of the hallmarks, shares some of the same mechanisms as aging. This could clarify the bidirectional relationship between cancer and aging [16].
The goal of this review is to better understand the potential central neurotoxic effects of cancer and its treatment on the neurocognitive aging process in older cancer survivors. To address this aim in a comprehensive way, we summarized the existing literature on neuroimaging, neuropsychological functioning, and neurodegenerative disorders in this population.

Search Strategy
A literature search was conducted in PubMed, Web of Science, and MEDLINE databases. See Supplementary S1 for an overview of the searches in the search engines. The search included articles exclusively in English, dated between 1 January 2000 and 12 June 2021. The three main key search terms selected were related to 'Neoplasm' and ['Neurocognition' or 'Neurodegeneration'] and 'Elderly'. Synonyms were searched based on the database-trees and added for each key term. MeSH-terms were utilized where available. See Supplementary S2 for the detailed search string. This systematic review is registered at: https://doi.org/10.17605/OSF.IO/TBDFP (accessed on 17 January 2023).

Data Extraction
Duplicate articles were removed through EndNote and uploaded to Rayyan as a screening measure. Studies were then categorized according to the measurements used to determine functioning (i.e., imaging studies, neuropsychological tests, or questionnaires/interviews). Some studies used a combination of measurements (imaging, cognitive testing, interviews/questionnaires) in their analysis. These studies were categorized based on the focus of the study (Appendix A Table A1 imaging studies, Table A2 cognitive studies,  Table A3 questionnaire studies). Specific neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, other dementia types or cerebrovascular conditions) following cancer or its treatment were separately described (Appendix B Table A4).
Information of author, publication year, study-design, cancer subtype, treatment type, comparison group, participants, mean age at diagnosis, mean age at baseline, measurements used, and the main findings relevant to the current protocol were extracted per study (Tables A1-A3).

Study Characteristics
The search identified a total of 8738 citations, of which 2813 were in the search engine Pubmed, and 5925 in Web of Science ( Figure 1). The duplicate articles were eliminated using EndNote, resulting in 7628 remaining articles. These studies were then uploaded to Rayyan and evaluated based on their title and abstract, and 7393 articles were excluded. Of the remaining articles, 235 were evaluated in detail. Four additional articles were identified by manually searching for studies that have cited these papers. This resulted in a final selection of 48 publications relating to the research question, which were divided into the different outcome categories (i.e., imaging studies, cognitive tests, questionnaires/interviews). Five studies (10%) primarily described imaging findings. Thirty-six studies (75%) assessed the neurocognitive impact of cancer and its treatment based on cognitive testing and seven (15%) based on questionnaires/interviews. Fourteen studies used a combination of measurements (imaging, cognitive testing, interviews/questionnaires) in their analysis.
Forty-eight studies explicitly reported on neurodegenerative diseases after cancer treatment, which are separately described (Figure 1).

Imaging Studies
Normal brain aging includes decreases in total brain volume, gray and white matter connectivity, and hippocampus volume changes [17]. Structural changes in the brain were found in older survivors of cancer compared to age-and education matched controls. These included gray matter volume loss in areas such as the basal ganglia and right superior frontal gyrus [18][19][20] and white matter changes in the corpus callosum, exceeding the normal aging process. These brain changes correlated with overall cognitive impairment as well as specific cognitive functions such as language processing, verbal fluency, processing speed, executive functions, visuospatial abilities, visual and verbal memories, and word recall [20].
In addition, functional changes in brain metabolism were also found in survivors after chemotherapy, chemoradiation, or tamoxifen treatment. These included hypometabolism in orbital frontal regions and hypermetabolism in the left postcentral gyrus, which correlated with worse executive functioning, working memory, and divided attention. These changes could reflect potential dysfunction in frontal-subcortical brain regions [21]. Hypoactivation of frontal areas is also seen in normal aging. Treatment can thus accelerate or mimic the effects of normal cognitive aging in survivors [22]. Interestingly, lower concentrations of myo-inositol were found in the brain after tamoxifen or estrogen treatments, while normal aging is associated with increased concentrations of myo-inositol, suggesting that brain aging might be favorably modulated by specific anti-hormone therapies [23]. Specifically, the most affected regions in cancer survivors were the frontal regions and changes in the basal ganglia consistent with regions affected by normal neurocognitive aging [18,20,21,23,24].

Neuropsychological Testing
A broad spectrum of tests (n = 36) measuring different cognitive domains were used in the studies (including attention, memory, processing speed, executive functioning, learning, language, visuospatial abilities, reaction time, psychomotor function, intelligence, and non-verbal function). Treatment-specific results were most often found.
Regarding CNS tumors, most often neurosurgery showed improvements in cognitive function [25,26]. One study showed no cognitive change after stereotactic radiotherapy for brain metastases [27], while another revealed lower or impaired cognitive scores more than 9 months after focal irradiation for glioblastoma [28].
In non-CNS tumor patients, local therapy (surgery or radiotherapy) did not have a substantial impact on cognition [29][30][31][32][33][34]. Only for sinonasal and gynecological cancers, impaired cognitive functioning was found after radiotherapy and/or surgery [19,35]. This can be explained as irradiation for sinonasal cancer, which is located close to the brain, which could indirectly affect the brain [19]. For the study on gynecologic cancers, local therapy, directly affected ovarian function, resulting in decline in estrogen levels, thus similarly affecting cognition as was seen by the studies on anti-hormone therapy [35].
Anti-hormonal therapy, specifically tamoxifen, resulted in worse learning (information processing), verbal memory, and executive functioning in cancer survivors compared to healthy controls [36][37][38][39]. ADT in prostate cancer resulted in worse cognitive performance, compared to healthy controls, specifically in executive function attention, memory, and information processing [30,[40][41][42][43], although not consistently replicated [44][45][46][47][48]. These deficits related to anti-hormonal therapy are strongest and most often found during and shortly after treatment [38,40]. A potential cognitive benefit was found of exogenous levothyroxine in thyroid cancer on the cognitive function of patients who lack endogenous thyroid hormone [49].
Chemotherapy negatively impacted cognitive processing speed, visual and verbal memory, spatial function, and attention in most studies [24,[50][51][52][53], although not consistently replicated [31,33,54]. One study found better recall in survivors that had received chemotherapy, but this was due to an age and treatment interaction as younger people were more often in better conditions and received chemo [32].
Inconsistent results were found when comparing studies that did not distinguish between specific treatments and/or cancer types. Some found similar trajectories of cognitive functioning compared to healthy controls [31,55,56], others found that cancer survivors in general have more cognitive impairment [57,58]. One study even showed spurious results of better memory and slower memory decline in older cancer survivors compared to healthy controls [59].

Interviews/Questionnaires
Divergent results were found in the studies on subjective cognitive complaints. There were studies that found no association between previous cancer diagnosis and self-reported cognitive complaints, maintaining good long-term self-reported cognitive complaints [61][62][63]. Two studies showed the opposite, that long-term survivors most often presented a higher rate of cognitive complaints [42,64]. Memory domains were most likely perceived as affected, specifically the ability to learn new information [38,42,58,65]. Loss of memory was more often reported in female breast cancer survivors or gynecologic cancers [35,66], and in patients with pre-existing cognitive or memory complaints [63,65]. One study investigated anti-hormonal therapy and found that tamoxifen users (but not exemestane users) reported increased attention/concentration complaints [60]. Chemotherapy studies more frequently reported loss of memory [65,66] or worse perceived concentration, or general cognitive abilities [36,63], although not always replicated [61].

Neurodegenerative Diseases following Cancer
Treatment-and cancer-specific results were most often found. Most studies found a decreased risk for AD or a delay in onset (but not progression) of PD in patients with skin cancer [18,[67][68][69]. Two studies found that skin cancer increased the risk of AD [70] or PD [71]. Divergent results were found for smoking-related cancers (i.e., lung, oral, larynx, pharynx, esophagus, stomach, pancreas, bladder, kidney, and cervical cancer). While some studies found a decreased risk of AD, PD, or stroke in these cancers [70][71][72][73][74], others found the opposite [75][76][77]. Hormone-related tumors (i.e., breast, uterus, and prostate cancer) were associated with decreased risk of developing AD or PD in some studies [76,78,79] while other studies found an increased risk [70] or no association [80,81].
In addition, differential effects for cancer treatments were found. The majority of studies found that the use of ADT resulted in increased risk of developing AD compared to no ADT treatment [82][83][84][85][86][87][88][89][90], with increasing risk in case of longer use [88], although not consistently replicated for AD or PD [91][92][93][94] or for cerebral infarction [95]. Regarding antihormonal therapy for breast cancer, one study found that aromatase inhibitors resulted in less risk of dementia than tamoxifen treatment [96] while another study found no difference between both treatments in the risk for dementia [97]. One study used a comparison group of no anti-hormonal treatment and found that tamoxifen and aromatase inhibitors were associated with decreased risk of AD and dementia [98]. Other treatments such as Bacillus Calmette-Guerin also showed reduced risk of AD and PD [73].
In comparison to radiotherapy in head and neck cancers, surgery had a comparable risk of consequent cerebrovascular events in one study [99], while in another, higher rates of cerebrovascular events were found in patients receiving radiotherapy compared to surgery alone [100]. One study showed that the use of some statins after radiotherapy could reduce this risk [101].
Some studies showed chemotherapy to be related to drug-induced dementia [102,103], while the risk of other types of dementia such as AD and vascular dementia were lower in patients that received chemotherapy [70,102]. Other studies found no associations [104][105][106][107].
When comparing studies that did not distinguish between specific treatments and/or cancer types, the majority of studies found that older cancer survivors have a lower risk of developing Alzheimer's disease (AD) compared to healthy controls [18,72,74,[78][79][80][108][109][110]. Some studies found no relevant association between cancer and risk of dementia or transient global amnesia [76,[111][112][113]. Comorbid factors such as socio-economic status and depression increased the risk of dementia [106,107].

Discussion
Given the rising incidence of cancer with age, research on the neurocognitive and neurodegenerative impact of cancer and its treatment in later life is important. Only a relatively small number of studies have focused on cancer survivors with a higher biological age. Overall, evidence was provided for functional and structural changes in the brain, specifically gray and white matter changes in the frontal regions and basal ganglia, consistent with changes in cognition, specifically working memory, executive functioning, and information processing. Anti-hormonal treatments were repeatedly associated with worse cognition (including tamoxifen) and sometimes with an increased risk of developing Alzheimer's disease (regarding ADT). Similarly, chemotherapy inconsistently resulted in cognitive changes or drug-induced dementia. Local surgery or radiotherapy was not associated with cognition in patients with non-CNS cancer. By contrast, local radiation to the head (cranial radiotherapy) did seem to play a cognitive role in patients with CNS cancer. For these patients, neurosurgery seemed to improve their cognition in the short-term.
Across studies, memory was frequently perceived as affected. When looking at the studies on neurodegenerative conditions in cancer survivors', divergent results were found for skin cancer and smoking-and hormone-related cancers, some increasing the risk of dementia and others showing a decrease in risk. When focusing on studies that did not distinguish between specific treatments or cancer types, most of these studies found that older cancer survivors have a lower risk of developing Alzheimer's disease (AD) compared to healthy controls.

Individual Risk Factors
As results are diverse, possible individual risk factors can be important to consider. These can include cancer types, treatment, genetic predisposition, age, comorbidities, and psychological and social factors [57,114]. As frailty increases with aging, due to physical, psychological-emotional, and cognitive functional deterioration, patients can cognitively deteriorate. This could even be accelerated, given that cancer patients often suffer from physiological and emotional sequelae related to their diagnosis and treatment.
A cancer diagnosis and the personal context (e.g., fatigue, sleep problems, hormonal changes, and tumor-related factors) can have indirect effects on cognition, which could be even more pronounced in older compared to younger people [3,115]. Relatedly, genetic predisposition can influence the relationship between cancer and cognition or neurodegeneration, such as genes associated with age-related cognitive decline [22,116]. These include genes encoding apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF) [114].
In addition, age-related comorbidities and frailty are an important consideration as well, as chronological age alone appears to be a poor predictor of the effects of treatment [117]. The combination of chronological age or age-related phenotypes such as frailty or cognitive reserve could better predict neurodegeneration in cancer survivors [36,115]. Increasing age also leads to an accumulation of multimorbidity, functional decline, and cognitive dysfunction that may degenerate into dementia symptoms [115,118]. Thus, survivors who are older and have less reserve pre-diagnosis could be more susceptible to reaching the threshold of cognitive deficits [64].
Psychological and social factors can also be a risk factor in cancer-related cognitive impairment or neurodegeneration [114]. The prevalence of mood disorders such as depression or anxiety is known to be high in adults aged 65 and above compared to younger adults [3,114]. Older people more often have decreased social activities which provides additional emotional and practical challenges such as loneliness, needs of caregiver support, transportation, and home care [119]. There is a relationship between social isolation and increased cancer mortality as well as poorer treatment tolerance [119].
Each of these risk factors (cancer, treatment, genetic predisposition, age, comorbidities, psychological and social factors) can lead to physiological toxic effects and can affect the aging brain [114]. However, not all older cancer patients develop cognitive effects, and the risk can depend on individual resilience factors [22]. Interestingly, brain changes can also be found in older cancer patients without decline in neuropsychological functioning [120]. In some cancer patients overactivation in the brain was found, which could suggest compensatory mechanisms.

Physiological Features of Aging
Cancer and aging are linked biological processes, and the diagnosis of cancer and its treatment can accelerate the aging process [121]. An overlapping pathway involved in aging, cancer, and treatment are inflammatory responses as they can trigger neurotoxic cytokines [22].
First, hormonal levels decrease with age and can more profoundly decrease when anti-hormonal therapies are prescribed as cancer treatment [22]. Hence, different effects have been found, dependent on the type of anti-hormonal treatment. Second, treatment such as chemotherapy can disrupt cellular processes and cell division resulting in increased inflammatory responses [114]. DNA damage and diminished DNA repair are markers of senescence and are found in age-related diseases such as PD, AS, and mild cognitive impairment [22]. Some chemotherapies have been shown to cross the blood-brain barrier and strengthen central neurotoxicity [22]. Telomere length is a marker of cellular age, stress, AD, cancer risk, and mortality. Certain cancer treatments influence telomere length, resulting in a common pathway between aging and cancer-related cognitive decline [22]. Senescent cells are also a biomarker of the frailty phenotypes that could increase the risk of cognitive decline [22].
These pathways can also result in overlapping brain changes affected by cancer treatment, neurocognitive aging, and neurodegeneration. While normal aging has a curvilinear process with most decline in older age, the slope can change due to individual risk factors [122]. Thus, even if cancer treatment has the same impact on the brain independent of age, the cognitive performance may change depending on the age of the individual and the slope of cognitive aging [122].

Gaps in Research and Future Directions
This review demonstrated that cancer diagnosis and treatment could have an adverse effect on cognition or neurodegeneration and inter-study differences were found. However, some limitations need to be mentioned. First, a common limitation in many studies was the relatively small sample size, raising questions on representativeness of the sample group in the general population. Second, studies often included selected sub-populations (e.g., excluding patients with too much comorbidity), which could result in a selection bias. For instance, the number of studies on patients with CNS tumors was limited. Most studies looked at the treatment of anti-hormone therapy or chemotherapy while the results on immune therapy and local therapy were limited. Third, different validated measures of cognitive function were used in different studies making it difficult to make a comparison. Given the wide scope of existing findings that we aimed to summarize, and the current lack of such comprehensive overview, we included both cognitive and dementia research to integrate different perspectives addressing potential accelerated neurocognitive aging. In this study, we conducted a systematic review covering different aspects. This was selected given that the existing data to date are too diverse and limited to perform a metaanalysis. More specifically, more than thirty different neuropsychological test materials were used to assess cognitive functioning, covering attention, memory, processing speed, executive functioning, learning, language, visuospatial abilities, reaction time, psychomotor function, intelligence, and non-verbal function. Moreover, different cancer populations were included, both non-CNS and CNS cancer types. The majority of studies covered either neuropsychological test assessments, or epidemiological studies on neurodegenerative diseases. Studies focusing on neuroimaging or questionnaire data only in the elderly population were rather limited.
A combination of imaging, cognitive testing, and subjective cognitive complaints gives the most information on the effects of cancer and treatment on cognition and neurodegeneration as some results may be very subtle. Fourth, not all studies described the different cancer treatments (or its timeline) in detail, which complicates the interpretation of treatment-specific effects. Finally, many studies did not use a control group without cancer (either healthy controls or cancer survivors who did not receive a specific treatment), making it difficult to compare to the general healthy population, thus concluding whether cancer and/or its treatment accelerated the normal aging process.
Future studies on the neurocognitive and neurodegenerative impact of cancer treatment should include sufficient numbers of older cancer survivors in order to capture variability in reserve and frailty and to highlight the effects of different treatments, biological processes and other chronic comorbidities.
Evaluating someone's individual risk for developing short-or long-term cognitive deficits or neurodegeneration in later life is important in creating a treatment plan. This can be done through a multidimensional assessment, having a predictive value in identifying a subgroup of cancer patients and older survivors that are at higher risk for cognitive decline, thus needing closer monitoring and intervention. More imaging studies will be critical in identifying brain structural links between cancer and neurocognitive aging. Research on treatments that have less toxic impact and provide more quality of life are essential as well. For those patients that do experience cognitive decline and neurodegeneration, rehabilitation programs and interventions should be created to support these cognitive losses. Through the understanding of specific risk factors for cognitive deficits in older cancer survivors, and by understanding the link between cancer treatment and the neurocognitive aging process, tools could be developed to identify patients more at risk for accelerated neurocognitive aging, neurodegeneration, or cognitive dysfunctions.

Conclusions
In this review, we provided a comprehensive overview of evidence related to potential accelerated brain aging, including neuroimaging, and neurocognitive and neurodegenerative disorders studies in older cancer survivors (>65 years). Evidence was found for functional and structural brain changes in multiple areas (frontal regions, basal ganglia, gray and white matter). Cognitive decline was mainly found in memory. Anti-hormonal treatments were repeatedly associated with cognitive decline (tamoxifen) and sometimes also with Alzheimer's disease (androgen deprivation therapy). Chemotherapy was inconsistently associated with later development of cognitive changes or dementia. Radiotherapy was not associated with cognition in non-central nervous system cancer but can play a role in patients with central nervous system cancer, Neurosurgery rather seemed to improve cognition in the short-term. These overall findings can be moderated by individual risk factors, which include brain cancer, hormone-related cancers, anti-hormonal therapy, chemotherapy, cranial radiation, genetic predisposition (e.g., APOE, COMT, BDNF), age, frailty and cognitive reserve, depression or post-traumatic distress, sleep, fatigue, and social factors. Based on the current state of the art, more research focusing on accelerated aging in older cancer patients is required to better understand the risks in subpopulations and the underlying mechanisms to improve tailored guidance and intervention studies.

Acknowledgments:
We are grateful to Anne Uyttebroeck for her support during the set-up of this process.       In long-term survivors, previous Tx may augment cognitive dysfunction associated with age-related brain changes -Domains affected: global cognition, attention, working memory, psychomotor speed, and executive functioning -Reflects potential dysfunction in frontal-subcortical brain region Table A3. Overview of self-report studies in older cancer survivors according to the systematic literature review.